title: Sequential activation of inflammatory signaling pathways during graft-versus-host disease (GVHD): early role for STAT1 and STAT3.
abstract: The aim of this study was to delineate the temporal and spatial sequence of STAT1 and STAT3 activation during development of GVHD following fully Major Histocompatibility Complex (MHC)-mismatched allogeneic Bone Marrow Transplantation (BMT). Activation of inflammatory signaling pathways in GVHD target organs was assessed by western blotting, phospho-flow cytometry and electromobility shift assays (EMSA). Development of GVHD was associated with significant expansion of phospho[p]-STAT1 and p-STAT3 expressing CD4(+) T cells and CD8(+) T cells. GVHD-specific STAT3/STAT1 activation preceded activation of Nuclear Factor-κB (NF-κB) and Mitogen Activated Protein Kinase (MAPK) and was associated with subsequent induction of STAT1 or STAT3-dependent inflammatory gene-expression programs (e.g. expression of IRF-1, SOCS1, IL-17). Our studies may help to establish a functional hierarchy of the signaling events leading to the development of GVHD and could be helpful in designing new molecularly targeted treatment approaches for GVHD.
authors.affiliation: University of Pittsburgh Cancer Institute, Department of Medicine, Division of Hematology-Oncology, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213-1863, United States.
authors.forename: Hui-Hui
authors.initials: HH
authors.lastname: Ma
authors.forename: Judy
authors.initials: J
authors.lastname: Ziegler
authors.forename: Cuiling
authors.initials: C
authors.lastname: Li
authors.forename: Antonia
authors.initials: A
authors.lastname: Sepulveda
authors.forename: Ahmed
authors.initials: A
authors.lastname: Bedeir
authors.forename: Jennifer
authors.initials: J
authors.lastname: Grandis
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lentzsch
authors.forename: Markus Y
authors.initials: MY
authors.lastname: Mapara
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000276:immunology*; D007249:Inflammation; D008099:Liver / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000276:immunology*; D015398:Signal Transduction; D013154:Spleen / Q000201:enzymology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
chemical_list: D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; D020929:Mitogen-Activated Protein Kinase Kinases